PROJECT SUMMARY {See instructions): This proposal applies a novel set of cognitive, neurobiological and molecular profiling approaches to the question of how to understand the concept of cognitive reserve in a rodent model of aging. An integrated set of experiments is proposed designed lo assess, mechanisms underlying differential cognitive trajectories observed over the lifespan of the rat at three different phases of the lifespan, young adult, middle age, and old. The experiments take advantage of technologies that cannot be used in humans at present, as well as those that can (such as cognitive tests and MRl imaging methods). These methods have not been applied in combination in the rodent previously, and involve high resolution MRl Imaging of the entire brain, cognitive tests that examine domains relevant to 8 brain regions in the temporal and frontal lobes (hippocampal regions CAI, CA3, dentate gyrus and the subiculum; temporal lobe regions perirhinal cortex and medial entorhinal cortex; frontal lobe regions anterior cingulate and prelimbic cortex), behavior-induced, single cell gene expression imaging in these 8 regions, and in 4 hippocampal subregions cell-specific whole transcriptome analyses. These procedures will be conducted in rats that are chosen on the basis of possessing behavioral performance scores that are high, average or low with respect to performance distributions from young, middle-aged and old rats. The present experiments have the potential to identify cell-specific RNA transcripts and behavior-activated circuits in brain regions that are critical for cognition, and that define how individuals segregate along a cognitive competence continuum throughout life. The combination of these methods will enable identification of those variables that are associated with more or less successful cognitive aging trajectories - a fundamental necessity if effective treatments are to be developed. The specific goals of this project are approached experimentally under two main aims. AIM 1 is to identify transcriptional patterns in hippocampal subregions that are associated with differential cognitive aptitudes across the lifespan. AIM 2 is to identify behavior-induced activity patterns in temporal and frontal lobe circuits associated with differential cognitive abilities, to identify what circuit characteristics are associated with successful cognitive outcomes during aging and the extent to which temporal and frontal lobes age independently. Together, the data collected in these experiments should identify targets useful in the development of strategies to optimize cognition during aging.